Reciprocal regulation of pulmonary and cardiac angiotensin-converting enzyme in rats with severe left ventricular hypertrophy.

OBJECTIVE: Numerous studies support the concept that cardiac angiotensin-converting enzyme (ACE) is involved in the pathophysiology of left ventricular hypertrophy. However, the pulmonary vasculature is considered to be the most prominent site of ACE expression. We thus examined the tissue specificity of ACE regulation in rats with severe cardiac pressure overload hypertrophy in transition to cardiac failure with secondary pulmonary hypertension. METHODS AND RESULTS: Rats were studied 12 weeks after banding of the ascending aorta (LVH, n = 20) that resulted in a 1.7-fold increase in left ventricular (LV) to body weight ratio. In addition, as compared to sham-operated rats (n = 20), we observed in LVH rats a 1.6-fold increase in right ventricular (RV) to body weight ratio, the development of pulmonary hypertension, and elevated plasma renin activities. Moreover, ACE mRNA and activity levels were more than 2-fold higher in both hypertrophied ventricles (P < 0.01, each). In contrast, pulmonary ACE mRNA and activity levels were markedly decreased in animals with LVH (more than 30%, respectively, P < 0.05 vs. sham), Interestingly, LV and RV ACE activity, as well as systolic pulmonary artery pressure and plasma renin activity, were all inversely related to pulmonary ACE activity. In order to differentiate the potential role of elevated renin in the down-regulation of pulmonary ACE, additional rats (n = 12) were treated with furosemide that resulted in a 8-fold rise in plasma renin activity, but only in a marginal decrease of pulmonary ACE mRNA levels and activity (-10% vs. sham (n = 8), P-value n.s.). CONCLUSIONS: The data indicate tissue specific reciprocal regulation of pulmonary and cardiac ACE in rats with cardiac pressure overload hypertrophy and pulmonary hypertension, a phenomenon that may potentially result in a partial shift of angiotensin II formation from the pulmonary to the cardiac circulation.

[Nephrotic syndrome as the initial symptom of Crohn disease]. / Nephrotisches Syndrom als Erstsymptom eines M. Crohn.

In february 1993, a now 54-year-old man presented with an increased serum-creatinine of 1.7 mg/dl known since september 1992 associated with peripheral edema. He reported painless and infrequent diarrhea during the previous 15 years. Clinically, he showed typical symptoms of a nephrotic syndrome. A renal biopsy revealed an amyloidosis. By further investigations the diagnosis of underlying Crohn's disease could be established. An ileocecal resection and a subsequent immunosuppressive therapy with azathioprine was performed. Following this procedure the serum-creatinine has meanwhile increased to 3.2 mg/dl with the proteinuria remaining stable. Furthermore, the patient developed a renal hypertension. However, at present the patient is otherwise asymptomatic and in a good general condition.

Alteration of growth responses in established cardiac pressure overload hypertrophy in rats with aortic banding.

We examined the acute effects of elevated wall stress, norepinephrine, and angiotensin II on cardiac protein synthesis as well as protooncogene expression in hearts with established pressure overload left ventricular hypertrophy. Isolated rat hearts with chronic hypertrophy (LVH) were studied 12 wk after ascending aortic banding when systolic function was fully maintained. New protein synthesis (incorporation of [3H]phenylalanine [Phe]) was analyzed in isolated perfused rat hearts after a 3-h protocol; c-fos, c-jun, c-myc, and early growth response gene-1 (EGR-1) mRNA levels (Northern blot) were studied over a time course from 15 to 240 min of perfusion. Under baseline conditions (i.e., before mechanical or neurohormonal stimulation), [3H]-Phe-incorporation (280 nmoles/gram protein/h) and protooncogene mRNA levels were similar in age-matched control and LVH hearts. However, hearts with chronic LVH were characterized by a markedly blunted or absent [3H]-Phe-incorporation after acute imposition of isovolumic systolic load (90 mmHg/gram left ventricle), as well as norepinephrine (10(-6)M), or angiotensin II infusion (10(-8)M plus prazosin 10(-7)M) compared with nonhypertrophied control hearts. Similarly, stimulation of LVH hearts with acute systolic load or norepinephrine was associated with a significantly blunted increase of protooncogene mRNA levels relative to control hearts. The blunted induction of c-fos mRNA in LVH hearts was not due to feedback inhibition, since cycloheximide perfusion of hearts exposed to elevated wall stress further increased the differences between age-matched control and LVH hearts. The data suggest that acute molecular growth responses to mechanical or neurohormonal stimulation are altered in rat hearts with established LVH relative to nonhypertrophied control hearts. This alteration of molecular adaptations in hearts with compensatory hypertrophy may prevent inappropriate excess cardiac growth in response to mechanical and neurohormonal stimuli.

[A severe course of leptospirosis with acute kidney failure and extensive icterus (Weil disease)]. / Schwerer Verlauf einer Leptospirose mit akutem Nierenversagen und ausgeprägtem Ikterus (Morbus Weil).

A 77-year-old man developed a fever up to 38.4 degrees C, with diarrhoea, acute renal failure (creatinine up to 8.7 mg/dl; urea up to 308 mg/dl) and marked jaundice (total bilirubin up to 24.3 mg/dl). In addition there was thrombocytopenia, conjunctivitis and epistaxis, as well as cerebral symptoms with somnolence and general slowing up. At first he was thought to have cholangitis resulting from previously diagnosed gall-stones, and he was therefore treated with ampicillin, 2 g two times daily, and metronidazole, 0.5 g two times daily. The fewer regressed, but the renal failure required haemodialysis and haemofiltration under strict fluid control. Endoscopy excluded obstructive jaundice, but a suspicion of inflammatory liver disease or possibly cirrhosis was raised in the differential diagnosis. Serology revealed an increased titre for Leptospira interrogans var. sejroe (1:200, later 1:1600). Liver biopsy finding was compatible with the diagnosis of leptospirosis. Because of the high inflammatory activity in the liver, 2 mega units of penicillin G were administered three times daily for six days. Gradually the renal functions and jaundice improved and, on discharge on the 36th day, the patient was again in generally good health, although creatinine and bilirubin values were still slightly elevated (1.7 mg/dl each).

[Value of ACE inhibitors in heart failure (clinical aspects)]. / Stellenwert von ACE-Hemmstoffen bei Herzinsuffizienz (Klinik).

The use of ACE-inhibitors in patients with severe congestive heart failure is established on the basis of the results of the CONSENSUS I-study, which has shown that ACE-inhibitors in patients in NYHA class IV not only have improved functional parameters, but also improved survival. Recently published controlled data from studies including patients with mild to moderate heart failure (SOLVD-study) show a significant improvement of mortality in this subgroup. Comparing placebo and ACE-inhibitors, the effect of ACE-inhibitors on mortality is due to a reduction of progression of pump failure. Comparing vasodilator-therapy (hydralazine/isosorbide dinitrate) and ACE-inhibition in the V-HeFT II-trial showed, despite a transient increase in ejection fraction and exercise capacity during the vasodilator-therapy, a significant improvement in survival in the patients treated with an ACE-inhibitor. This was achieved by a reduction of the incidence of sudden cardiac death. From these recent data it can be concluded that ACE-inhibition is the therapy of choice in patients with mild to severe heart failure.

[Left ventricular hypertrophy: favorable or unfavorable compensatory mechanisms?]. / Linksventrikuläre Hypertrophie: Günstiger oder ungünstiger Kompensationsmechanismus?

Myocardial hypertrophy serves, at least initially, a compensatory function to maintain wall stress and oxygen consumption within the normal range in hemodynamic overload of the ventricle which preserves systolic cardiac performance. These favorable changes of the myocardium with regard to systolic pump capacity of the left ventricle against an increased load, leads early in this adaptive process to unfavorable hemodynamic changes. As a result of these functional cardiac consequences of left ventricular hypertrophy develops impaired diastolic filling with diminished diastolic dimensions. Left ventricular hypertrophy is per se associated with poor prognosis due to an increased risk of sudden death and the development of congestive heart failure. Subendocardial ischemia may play a major role in the genesis of these events. As a consequence, therapeutic interventions should not only decrease the hemodynamic load of the left ventricle but also lead to a regression of left ventricular hypertrophy which is an independent risk factor in hypertension.

Hormones in heart failure--regulation and counterregulation.

In chronic heart failure, neurohumoral mechanisms play an important role in the regulation of cardiac performance directly, by influencing systolic and diastolic function of the myocardium, and indirectly, by modulating pre- and afterload. The important vasoconstrictor, fluid and sodium retaining factors are the renin-angiotensin-aldosterone system, sympathetic nerve activity and vasopressin; the vasodilator, volume and sodium eliminating factors are atrial natriuretic peptide, vasodilator prostaglandins, such as prostacyclin and prostaglandin E2, dopamine, bradykinin and, possibly, endothelium-derived relaxing factor and vasoactive intestinal peptide. There is evidence from experimental and clinical studies that sympathetic nerve activity is stimulated in the early phase of the disease, as is the secretion of atrial natriuretic peptide, which increases in proportion to an increased preload. In early or mild heart failure, atrial natriuretic peptide suppresses the activity of the renin-angiotensin-aldosterone system, may prevent an increase in peripheral vascular resistance and preserves renal blood flow. In more severe heart failure, the renin-angiotensin-aldosterone system is activated, leading to an increase of peripheral and renal vascular resistance and fluid and sodium retention. This is associated with an increased production of vasodilator prostaglandins. In severe heart failure, mostly in connection with hyponatraemia, a non-osmolar inappropriately high secretion of vasopressin can be demonstrated. These findings suggest that early therapeutic intervention to suppress unfavourable neurohumoral mechanisms or to support protective factors, such as atrial natriuretic peptide, may be of particular importance in the treatment of congestive heart failure, delaying progression of the disease, which would improve survival.

[Lipid status and basal steroid hormone level following 16 weeks of lovastatin therapy in primary hypercholesterolemia]. / Lipidstatus und basale Steroidhormonspiegel nach 16 Wochen Lovastatintherapie bei primärer Hypercholesterinämie.

We examined the effect of a 16 week therapy with the HMG CoA reductase inhibitor lovastatin in 29 patients (mean age 43 years) with primary hypercholesterolemia. All patients had cholesterol levels above 250 mg/dl (mean 348 +/- 96 mg/dl) inspite of a lipid lowering diet and a therapy with conventional lipid lowering drugs during a three month screening period. After 4 weeks on placebo 20 mg lovastatin was given orally for 4 weeks. If total cholesterol exceeded 200 mg/dl the dose of lovastatin was increased monthly by 20 mg up to the maximal dose of 80 mg/day. After 16 weeks lipid values changed compared with the placebo period: total-cholesterol -25%, triglycerides -8.6%, LDL-cholesterol -31%, APO B -25%, HDL-cholesterol +5.8%, APO AI +0.8%, total-cholesterol/HDL-cholesterol -25%. There was a significant improvement of lipid parameters after lovastatin therapy compared with conventional lipid lowering drugs at the end of the screening period. Lovastatin was well tolerated. A small and reversible rise of transaminases and/or creatinine kinase was observed in 6 patients. Basal levels of ACTH in the morning increased significantly during lovastatin therapy within the normal range. This observation was more frequent in females (10/12) than in males (10/17).

[Role of prostaglandins in regulation of kidney function in heart failure]. / Bedeutung von Prostaglandinen bei der Regulation der Nierenfunktion bei Herzinsuffizienz.

Conditions like heart failure that augment the activity of neurohumoral mechanisms i.e. the renin-angiotensin systems, sympathetic nerve activity and vasopressin secretion are commonly associated with a decreased effective blood volume and a reduced renal perfusion. This leads to an increased dependence of renal hemodynamics on endogenous renal prostaglandin synthesis as a vasodilator and natriuretic counter-regulating system. We investigated the role of prostaglandins in renal functional control in an experimental setting of congestive heart failure by chronic inhibition of cyclooxygenase by indomethacin. In chronic moderate heart failure plasma levels of prostaglandin E2 and prostacyclin were unchanged whereas the urinary excretion of prostaglandin E2 was significantly increased, indicating an augmented synthesis within the kidney (Figures 1 to 3). After inhibition of prostaglandin synthesis we observed a profound increase of renal vascular resistance associated with a reduction of effective renal plasma flow and renal blood flow. This was mainly due to a constriction of the vas afferens of the glomerulum. This led to an impairment of renal function indicated by an increase of serum creatinine and blood urea nitrogen associated with a reduction of urinary flow and fluid retention (Figures 4 and 5). We also studied in a randomized, double-blind, placebo-controlled, parallel-group trial in 40 patients with congestive heart failure effects of acetylsalicylic acid (500 mg t.i.d.) on renal functional parameters. In patients with normal sodium intake acetylsalicylic acid reduced urinary prostaglandin E2 concentration by 37% which led to a reduction of daily urinary sodium excretion by 29% in comparison to placebo (Figure 6). These results clearly show the importance of vasodilator prostaglandins in the regulation of kidney function in heart failure where inhibition of cyclooxygenase results in profound deterioration of renal perfusion and kidney function and retention of fluid and sodium.

Role of neuroendocrine mechanisms in the pathogenesis of heart failure.

In chronic heart failure, neurohumoral mechanisms play an important role in the regulation of cardiac performance by direct influences on systolic and diastolic function of the myocardium, and indirectly, by modulation of pre- and afterload. Important vasoconstrictor, fluid- and sodium-retaining factors are the renin-angiotensin-aldosterone system, sympathetic nerve activity, and vasopressin; vasodilator, volume, and sodium-eliminating factors are atrial natriuretic peptide, vasodilator prostaglandins like prostacyclin and prostaglandin E2, dopamine, bradykinin, and possibly, endothelial derived relaxing factor (EDRF). There is evidence from experimental and clinical studies that the sympathetic nerve activity is stimulated in the early phase of the disease, as well as is the secretion of atrial natriuretic peptide which increases in relation to a rise in preload. In early or mild heart failure, atrial natriuretic peptide suppresses the activity of the renin-angiotensin-aldosterone system, which may prevent an increase in peripheral vascular resistance and preserve renal blood flow. In more severe heart failure, the renin-angiotensin-aldosterone system is activated, leading to an increase of peripheral and renal vascular resistance and fluid and sodium retention. This is associated with an increased production of vasodilator prostaglandins. In severe heart failure, mostly in connection with hyponatremia, a nonosmolar, inappropriately high secretion of vasopressin can be demonstrated. These findings suggest that early interventions in order to suppress unfavorable neurohumoral mechanisms or to support protective factors like atrial natriuretic peptide may be of particular importance in the treatment of congestive heart failure with the aim of a retardation of the progression of the disease, which would result in an improvement of survival.

[ACE inhibition: mechanisms of cardioprotection in chronic experimental heart failure]. / ACE-Hemmung: Mechanismen einer Kardioprotektion bei chronischer experimenteller Herzinsuffizienz.

In 1984 we demonstrated in an animal model of chronic congestive heart failure due to rapid right ventricular pacing in chronically instrumented dogs, that the inhibition of the renin-angiotensin-aldosterone system by captopril from the onset of pacing has beneficial effects on hemodynamic and neurohumoral mechanisms. In contrast to control animals, dogs on a chronic therapy with the ACE-inhibitor showed no significant increase in peripheral vascular resistance, a reduced decline of cardiac output and no significant increase of mean pulmonary arterial pressure. Chronic ACE-inhibition led to a significant reduction of the secretion of aldosterone, to an attenuation of the activation of the sympathetic activity and to a prevention of inappropriate stimulation of vasopressin secretion. This was associated with a reduction in symptoms and a lack of fluid retention, whereas control animals developed pleural infusions and ascites. Similar beneficial effects have been demonstrated in rats following myocardial infarction during a long-term therapy with captopril on hemodynamic parameters, heart size, and survival. Thus, early inhibition of the renin-angiotensin-aldosterone system in heart failure may be an attractive approach for treatment in patients with ventricular dysfunction even before symptoms develop.

[Renin, aldosterone and prostaglandins in heart failure]. / Renin, Aldosteron und Prostaglandine bei Herzinsuffizienz.

In heart failure, neurohumoral factors are important determinants of left-ventricular function, not only by direct mechanisms on the myocardium, but also by indirect effects through modulation of pre- and afterload. In experimental models of heart failure, as well as in patients with cardiac dysfunction, it has been demonstrated in the early phase of the disease that the sympathetic activity and the secretion of atrial natriuretic peptide are stimulated. This is associated with an increased synthesis of vasodilator prostaglandins in the kidney, predominately prostaglandin E2. Prostaglandin E2 plays an important role by its vasodilator and natriuretic properties in preserving renal blood flow, natriuresis and diuresis. The stimulation of the secretion of atrial natriuretic peptide in relatively moderate heart failure leads to a suppression of the activation of the renin-angiotensin-aldosterone system. In more severe heart failure vasoconstrictor, sodium and water-retaining mechanisms like the renin-angiotensin-aldosterone system are activated with the consequence of an increase of systemic vascular resistance, a reduction of renal blood flow, and an increased fluid retention. The inhibition of cyclooxygenase, leading to a blockade of the synthesis of prostaglandins, leads in early heart failure to a dramatic change in renal blood flow with an increase of renal vascular resistance and a decrease of renal perfusion which causes renal functional impairment.